This is a resubmission of a five year application to develop powerful methodologies in psychiatric genetics. Specifically to: (1) incorporate models of diagnostic stability into the genetic models to permit explicit modeling of diagnostic error and clinical heterogeneity within linkage analyses; (2) implement procedures for the multivariate analysis of quantitative and qualitative traits in nuclear families; (3) incorporate the analysis of follow-up data into genetic models to allow for diagnostic evaluations at multiple points in time; (4) investigate the utility of the MOD score (maximized lod score) in linkage analyses of complex traits. This aim follows extensive simulation study in which the MOD score method performed the best for detecting linkage for an oligogenic trait, and theoretical work is now needed for further exploration; (5) examine the optimal way to use association between a genetic marker and a trait to localize genes once they are detected; (6) develop efficient computer programs which implement these procedures and add them to our computer library and apply these new techniques to a number of currently existing data sets, including studies of Affective Disorder and Alcoholism. Long term objectives are to develop realistic genetic and non-genetic transmission models of the familial distributions of psychiatric illness, develop tests of nosological hypotheses and resolve phenotypic heterogeneities, develop techniques to detect specific environmental and genetic factors, provide documented computer programs to the scientific community, and collaborate with others to study a broad spectrum of psychiatric and medical disorders. Methods include theoretical, computer implementation and simulation and data analysis. First, theoretical issues in genetic epidemiology and linkage analysis will be resolved, these advances will then be extended and numerical techniques improved. Next, computer programs will be implemented and simulations used to assess operating characteristics. Finally, methods will be applied to data. This research will enable the definition of more etiologically homogeneous subgroups of affected individuals, the characterization of specific modes of transmission, improved risk prediction, the discovery of relevant pre-morbid characteristics. The research should also increase the power of linkage analysis to detect abnormal genes.